Genetic Variant CARD8:c.-44+3552T>C (chr19-48245971-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001184900.3(CARD8):c.-44+3552T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 151,238 control chromosomes in the GnomAD database, including 30,310 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.63 ( 30310 hom., cov: 31)

Consequence

CARD8
NM_001184900.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.31

Publications

10 publications found

Variant links:

Genes affected

CARD8 (HGNC:17057): (caspase recruitment domain family member 8) The protein encoded by this gene belongs to the caspase recruitment domain (CARD)-containing family of proteins, which are involved in pathways leading to activation of caspases or nuclear factor kappa-B (NFKB). This protein may be a component of the inflammasome, a protein complex that plays a role in the activation of proinflammatory caspases. It is thought that this protein acts as an adaptor molecule that negatively regulates NFKB activation, CASP1-dependent IL1B secretion, and apoptosis. Polymorphisms in this gene may be associated with a susceptibility to rheumatoid arthritis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2010]

CARD8 Gene-Disease associations (from GenCC):

inflammatory bowel disease 30
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CARD8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.06).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184900.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CARD8	NM_001184900.3	MANE Select	c.-44+3552T>C	intron	N/A	NP_001171829.1
CARD8	NM_001351782.2		c.-44+104T>C	intron	N/A	NP_001338711.1
CARD8	NM_001184901.1		c.-44+3780T>C	intron	N/A	NP_001171830.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CARD8	ENST00000651546.1	MANE Select	c.-44+3552T>C	intron	N/A	ENSP00000499211.1
CARD8	ENST00000520153.5	TSL:1	c.-44+3552T>C	intron	N/A	ENSP00000428736.1
CARD8	ENST00000520753.5	TSL:1	c.-44+3552T>C	intron	N/A	ENSP00000429839.1

Frequencies

GnomAD3 genomes

AF:

0.626

AC:

94690

AN:

151154

Hom.:

30285

Cov.:

show subpopulations

Gnomad AFR

AF:

0.762

Gnomad AMI

AF:

0.454

Gnomad AMR

AF:

0.632

Gnomad ASJ

AF:

0.632

Gnomad EAS

AF:

0.662

Gnomad SAS

AF:

0.660

Gnomad FIN

AF:

0.487

Gnomad MID

AF:

0.614

Gnomad NFE

AF:

0.561

Gnomad OTH

AF:

0.629

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.626

AC:

94749

AN:

151238

Hom.:

30310

Cov.:

AF XY:

0.625

AC XY:

46139

AN XY:

73854

show subpopulations

African (AFR)

AF:

0.762

AC:

31440

AN:

41262

American (AMR)

AF:

0.632

AC:

9583

AN:

15166

Ashkenazi Jewish (ASJ)

AF:

0.632

AC:

2196

AN:

3472

East Asian (EAS)

AF:

0.662

AC:

3412

AN:

5154

South Asian (SAS)

AF:

0.660

AC:

3170

AN:

4806

European-Finnish (FIN)

AF:

0.487

AC:

4974

AN:

10220

Middle Eastern (MID)

AF:

0.585

AC:

172

AN:

294

European-Non Finnish (NFE)

AF:

0.561

AC:

38058

AN:

67854

Other (OTH)

AF:

0.634

AC:

1331

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1773

3545

5318

7090

8863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

784

1568

2352

3136

3920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.594

Hom.:

11334

Bravo

AF:

0.640

Asia WGS

AF:

0.690

AC:

2399

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.014

(source)

DANN

Benign

0.45

PhyloP100

-4.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over